Hypertriglyceridemia, the most common dyslipidemia in patients with diabetes and the metabolic syndrome, is usually associated with low levels of HDL cholesterol and has been proposed as an independent risk factor for development of cardiovascular disease. However, clinical intervention data have failed to unambiguously establish the benefits of triglyceride-reduction medications. Moreover, laboratory studies have not shown significant atherosclerosis progression in non-diabetic animals with increased circulating triglyceride levels. The Project Leader has created novel mouse models of hypertriglyceridemia and greater lipolysis along the endothelial surface, and in collaboration with the co-investigator has shown that diabetes leads to defective atherosclerosis regression. We will focus on three key unresolved issues: i) Does hypertriglyceridemia in concert with diabetes affect HDL composition and function? ii) Can we learn about the functional requirements for effective HDL function by studying patients with rare diseases leading to low HDL cholesterol levels? iii) Does hypertriglyceridemia diabetes prevent regression of atherosclerosis in animals with low levels of circulating LDL? Our specific aims are: Aim 1. Determine the impact of key HDL-regulating enzymes and hypertriglyceridemia on HDL function and particle number in humans and mice. We will use genetically modified mice to study the effects of hypertriglyceridemia and CETP on HDL composition and function. In addition, the effects of hyperglycemia will be assessed in diabetic mice with and without glucose reduction. HDL changes in the animals will be compared with those in humans with lipoprotein lipase or lecithin acyl transferase deficiency and hypertriglyceridemia. Aim 2. Establish the effects of hypertriglyceridemia on regression of atherosclerotic lesions in a mouse model of diabetes. We will create mice with atherosclerosis diabetes and study regression in the presence of hypertriglyceridemia and increased vascular wall TG lipolysis. This will involve the use of adenoviral-mediated LDL reduction and aortic transplantation. Overall, these studies will define the relationships among hypertriglyceridemia, hyperglycemia, HDL composition and function, and vascular disease.